Oligonucleotide compositions and methods of use thereof

Abstract

Among other things, the present disclosure provides USH2A oligonucleotides, and compositions and methods of use thereof, for preventing and/or treating various conditions, disorders or diseases. In some embodiments, provided USH2A oligonucleotides comprise nucleobase modifications, sugar modifications, internucleotidic linkage modifications and/or patterns thereof, and have improved properties, activities and/or selectivities. In some embodiments, the present disclosure provides USH2A oligonucleotides, compositions and methods for preventing and/or treating USH2A-related conditions, disorders or diseases, such as Usher Syndrome (e.g., Usher Syndrome Type 2A), atypical Usher syndrome, or nonsyndromic retinitis pigmentosa.

1 .- 26 . (canceled) 
     
     
         27 . A chirally controlled oligonucleotide composition comprising a plurality of oligonucleotides, wherein the oligonucleotides share:
 1) a common base sequence,   2) a common pattern of backbone linkages, and   3) a common pattern of backbone chiral centers,   wherein the composition is enriched, relative to a substantially racemic preparation of oligonucleotides sharing the common base sequence and pattern of backbone linkages, for oligonucleotides of the plurality, and   wherein:   oligonucleotides of the plurality each independently comprise a phosphorothioate internucleotidic linkage,   oligonucleotides of the plurality each independently comprise a non-negatively charged internucleotidic linkages, and   the base sequence comprises at least 15 contiguous nucleobases of a base sequence that is at least 75% identical or complementary to a base sequence of an USH2A gene or a transcript thereof.   
     
     
         28 . (canceled) 
     
     
         29 . The composition of  claim 27 , wherein oligonucleotides of the plurality share the same linkage phosphorus stereochemistry at 5 or more chiral internucleotidic linkages. 
     
     
         30 . (canceled) 
     
     
         31 . The composition of  claim 29 , wherein about 30-100% of all oligonucleotides within the composition that share the common base sequence are oligonucleotides of the plurality. 
     
     
         32 .- 33 . (canceled) 
     
     
         34 . A method for preventing, treating or ameliorating an USH2A-related condition, disorder or disease and/or preventing, slowing the onset, development and/or progress, and/or treating an USH2A-related condition, disorder or disease in a subject susceptible thereto or suffering therefrom, comprising administering to the subject a therapeutically effective amount of a composition of  claim 27 . 
     
     
         35 . The method of  claim 34 , wherein the condition, disorder or disease is Usher Syndrome. 
     
     
         36 . (canceled) 
     
     
         37 . A method for increasing the level of skipping of a deleterious exon in an USH2A gene transcript or its gene product in a cell, comprising contacting the cell with a composition of  claim 27 . 
     
     
         38 .- 44 . (canceled) 
     
     
         45 . The composition of  claim 27 , wherein oligonucleotides of the plurality consists of or comprises a structure of 5′-a first region-a second region-a third region-3′, wherein each of the regions independently comprises one or more nucleosides. 
     
     
         46 . The composition of  claim 45 , wherein the first region comprises 5 or more nucleosides. 
     
     
         47 . The composition of  claim 46 , wherein the first region comprises two or more 2′-F modified sugars. 
     
     
         48 . The composition of  claim 47 , wherein the second region comprises two or more nucleosides. 
     
     
         49 . The composition of  claim 48 , wherein the second region comprises one or more 2′-F modified sugars and one or more 2′-OR modified sugars, wherein R is optionally substituted C 1-6  aliphatic. 
     
     
         50 . The composition of  claim 49 , wherein the third region comprises 5 or more nucleosides. 
     
     
         51 . The composition of  claim 50 , wherein the third region comprises two or more 2′-F modified sugars. 
     
     
         52 . The composition of  claim 51 , wherein the first region comprises one or more Sp phosphorothioate internucleotidic linkages. 
     
     
         53 . The composition of  claim 52 , wherein the first region comprises one or more non-negatively charged internucleotidic linkages. 
     
     
         54 . The composition of  claim 53 , wherein the second region comprises one or more Sp phosphorothioate internucleotidic linkages. 
     
     
         55 . The composition of  claim 54 , wherein the second region comprises one or more non-negatively charged internucleotidic linkages. 
     
     
         56 . The composition of  claim 55 , wherein the third region comprises one or more Sp phosphorothioate internucleotidic linkages. 
     
     
         57 . The composition of  claim 56 , wherein the third region comprises one or more non-negatively charged internucleotidic linkages. 
     
     
         58 . The composition of  claim 57 , wherein oligonucleotides of the plurality are capable of increasing the level of skipping of a deleterious exon in an USH2A gene transcript or a gene product thereof, wherein the deleterious exon is associated with Usher Syndrome.